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Prolyl hydroxylase domain protein 3 and asparaginyl hydroxylase factor inhibiting
HIF-1 levels are predictive of tumoral behavior and prognosis in hepatocellular
carcinoma
#MMPMID28099905
Ma M
; Hua S
; Li G
; Wang S
; Cheng X
; He S
; Wu P
; Chen X
Oncotarget
2017[Feb]; 8
(8
): 12983-13002
PMID28099905
show ga
Hypoxia-inducible factors (HIFs) are key regulators in oxygen homeostasis. Their
stabilization and activity are regulated by prolyl hydroxylase domain (PHD)-1,
-2, -3 and factor inhibiting HIF (FIH). This study investigated the relation
between these oxygen sensors and the clinical behaviors and prognosis of
hepatocellular carcinoma (HCC). Tissue microarray and RT-PCR analysis of tumor
tissues and adjacent non-tumor liver tissues revealed that mRNA and protein
levels of both PHD3 and FIH were lower within tumors. The lower expression of
PHD3 in tumor was associated with larger tumor size, incomplete tumor
encapsulation, vascular invasion and higher Ki-67 LI (p < 0.05). The lower
expression of FIH in tumor was associated with incomplete tumor encapsulation,
vascular invasion, as well as higher TNM stage, BCLC stage, microvascular density
and Ki-67 LI (p < 0.05). Patients with reduced expression of PHD3 or FIH had
markedly shorter disease-free survival (DFS), lower overall survival (OS), or
higher recurrence (p < 0.05), especially early recurrence. Patients with
simultaneously reduced expression of PHD3 and FIH exhibited the least chance of
forming tumor encapsulation, highest TNM stage (p < 0.0083), lowest OS and
highest recurrence rate (p < 0.05). Multivariate analysis indicated that a lower
expression of FIH independently predicted a poor prognosis in HCC. These findings
indicate that downregulation of PHD3 and FIH in HCC is associated with more
aggressive tumor behavior and a poor prognosis. PHD3 and FIH may be potential
therapeutic targets for HCC treatment.
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